tbuckley/cabot-search huggingface dataset:
Adjuvant dabrafenib plus trametinib (D + T) versus placebo in patients with resected stage III <i>BRAF</i><sup>V600</sup>-mutant melanoma: Updated 5-year distant metastases-free survival (DMFS) analysis of COMBI-AD.
Authors: Dirk Schadendorf, Axel Hauschild, Mario Mandalà, John M. Kirkwood, Caroline Robert, Jean-Jacques Grob, Paul D. Nathan, Michael A. Davies, Hiya Banerjee, Rohan Shah, Mike R. Lau, Reinhard Dummer, Georgina V. Long
Journal: Journal of Clinical Oncology (2022)

9563 Background: DMFS is an important endpoint for patients with stage III cutaneous melanoma, as delaying or preventing systemic disease is associated with improved clinical and patient-reported outcomes. Prior results from the phase 3 COMBI-AD trial (NCT01682083) showed 5-year DMFS rates of 65% with adjuvant D + T vs 54% with placebo (PBO; hazard ratio [HR] = 0.55; 95% CI: 0.44-0.70). An analysis of DMFS by AJCC-7 stages IIIA-C suggested a similar benefit of D + T vs PBO regardless of stage (Dummer R et al. N Engl J Med. 2020). Here, we report 5-year DMFS rates by AJCC-8 stages IIIA-D, other prognostic subgroups, and results of a regression tree analysis with DMFS. Methods: Patients with resected AJCC-7 stage III BRAF V600E/K -mutant melanoma were randomized to either D (150 mg twice daily) + T (2 mg once daily) or 2 matched PBOs for 12 months. Primary endpoint was relapse-free survival (RFS); DMFS was a secondary endpoint. Kaplan-Meier survival analyses were performed to assess the long-term benefits for DMFS rates with D + T vs PBO. The regression tree analysis (data cutoff: 5 years) for all patients (N = 870) evaluated potential prognostic/predictive factors of long-term DMFS including baseline age, sex, region, BRAF mutation type, body mass index, lactate dehydrogenase levels, ECOG, T and N categories, histology, primary tumor ulceration, treatment type, number of lymph nodes with metastases, tumor mutational burden, and interferon-gamma gene expression signature (IFN-γ GES). Results: At 5 years, DMFS rates were higher for patients with AJCC-8 stages IIIB-D disease receiving adjuvant D + T vs PBO (table). Five-year DMFS rates also favored D + T vs PBO in subgroups of patients with microscopic or macroscopic lymph node involvement (table) and those with or without primary tumor ulceration and/or in-transit metastases. A regression tree revealed T and N stage, treatment type, and IFN-γ GES as important variables defining 5-year DMFS subgroups. Conclusions: In this retrospective analysis, adjuvant D + T provided long-term DMFS benefit vs PBO in stage IIIB-D patients with resected BRAF V600E/K -mutant melanoma. Key clinical and patient factors impacting DMFS were similar to prior RFS findings (ESMO 2021; Robert C et al. Ann Oncol. 2021) and included T and N stage, treatment type, and IFN-γ GES. These results further validate the robust long-term clinical benefit of adjuvant D + T for patients with melanoma. Clinical trial information: NCT01682083. [Table: see text]
SARS-CoV-2 Evolution and Immune Escape in Immunocompromised Patients
Authors: Erin M Scherer, Ahmed Babiker, Max W Adelman, Brent Allman, Autum Key, Jennifer M Kleinhenz, Rose M Langsjoen, Phuong-Vi Nguyen, Ivy Onyechi, Jacob D Sherman, Trevor W Simon, Hannah Soloff, Jessica Tarabay, Jay Varkey, Andrew S Webster, Daniela Weiskopf, Daniel B Weissman, Yongxian Xu, Jesse J Waggoner, Katia Koelle, Nadine Rouphael, Stephanie M Pouch, Anne Piantadosi
Journal: New England Journal of Medicine (2022)
Acute and post-acute COVID-19 presentations in athletes: a systematic review and meta-analysis
Authors: Italo Ribeiro Lemes, Fabiana Infante Smaira, Willian J. D. Ribeiro, Natalia Koenig Favero, Luciana Diniz Nagem Janot Matos, Ana Lúcia de Sá Pinto, Eimear Dolan, Bruno Gualano
Journal: British Journal of Sports Medicine (2022)

Objective To describe acute/postacute COVID-19 presentations in athletes. Design Systematic review and meta-analysis. Data sources The search was conducted in four databases (MEDLINE, EMBASE, SCOPUS, SPORTDiscus) and restricted to studies published from 2019 to 6 January 2022. Eligibility criteria for selecting studies Studies were required to (1) include professional, amateur or collegiate/university athletes with COVID-19; (2) present data on acute/postacute COVID-19 symptoms and (3) have an observational design. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal tools. Results 43 studies with 11 518 athletes were included. For acute presentation, the pooled event rates for asymptomatic and severe COVID-19 were 25.5% (95% CI: 21.1% to 30.5%) and 1.3% (95% CI: 0.7% to 2.3%), respectively. For postacute presentations, the pooled estimate of persistent symptoms was 8.3% (95% CI: 3.8% to 17.0%). Pooled estimate for myocardial involvement was 5.0% (95% CI: 2.5% to 9.8%) in athletes undergoing any cardiac testing, and 2.5% (95% CI: 1.0% to 5.8%) in athletes undergoing MRI, although clinical symptoms were not characterised. None of the studies with a control group (eg, non-infected athletes) could confirm a causal relationship between COVID-19 and myocardial involvement. Conclusion This broad characterisation of COVID-19 presentations in athletes indicates that ~94% exhibited mild or no acute symptoms. The available evidence did not confirm a causal relationship between COVID-19 and myocardial involvement. A small proportion of athletes experienced persistent symptoms while recovering from infection, which were mostly mild in nature, but could affect return-to-play decisions and timing.
Implementation of robotic radical cystectomy with intracorporeal neobladder reconstruction: Step-by-step description of the technique
Authors: M.C. Sighinolfi, S. Assumma, E. Morini, A. Del Nero, I. Piacentini, B. Mangiarotti, M. Maggioni, S. Puliatti, S. Picozzi, G. Bozzini, S. Micali, B. Rocco
Journal: European Urology (2022)
Renal functional and cardiovascular outcomes of partial nephrectomy versus radical nephrectomy for renal tumors: A systematic review and meta-analysis
Authors: M-A. Ochoa-Arivzo, A. Diaz Gonzalez-Colmenero, R. Pallares-Mendez, L.R. García-Chairez, M. Garcia-Campa, D.E. Cervantes-Miranda, H.H. Plata-Huerta
Journal: European Urology (2022)
Laparoscopic vs. Robot-assisted nephroureterectomy: Propensity score matched comparison of surgical and early oncologic outcomes
Authors: A. Brassetti, F. Proietti, U. Anceschi, A. Bove, M.C. Ferriero, R. Mastroianni, L. Misuraca, G. Tuderti, C. Leonardo, G. Simone
Journal: European Urology (2022)
RARE-15. Astroblastoma, <i>MN1</i> altered comprises two molecularly and clinically distinct subgroups defined by the fusion partners <i>BEND2</i> and <i>CXXC5</i>
Authors: Felix Schmitt-Hoffner, Johannes Gojo, Monika Mauermann, Katja von Hoff, Martin Sill, Damian Stichel, David Capper, Arnault Tauziede-Espariat, Pascale Varlet, Kenneth Aldape, Zied Abdullaev, Andrew M Donson, Ulrich Schüller, Matija Snuderl, Sebastian Brandner, Maria Łastowska, Joanna Trubicka, Evelina Miele, Jasper van der Lugt, Jens Bunt, Christof Kramm, Michal Zapotocky, Felix Sahm, Andrey Korshunov, Natalie Jäger, Stefan M Pfister, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract In the recent 5th edition of the WHO classification of CNS tumors, ‘Astroblastoma, MN1 altered’ is recognized a distinct brain tumor type, occurring in children and young adults. Due to its rarity and novelty, little is known about clinical and molecular traits. Therefore, we initiated an international effort and collected tissue samples, clinical and molecular data from 176 patients with Astroblastoma, MN1 altered, identified by their distinct DNA methylation profiles. DNA methylation-based t-SNE clustering analyses revealed that Astroblastoma, MN1 altered tumors form one distinct main cluster (n=158) showing MN1:BEND2 and single cases with EWSR1:BEND2 fusions and a further adjacent, but distinct smaller cluster (n=18) mostly defined by MN1:CXXC5 fusions. Both fusion partner-defined groups show a median age of 12 years but distinct copy-number aberrations, characteristically a gain of chromosome 5 in one third of the CXXC5-fused group and a loss of chromosome 16q in one third of BEND2-fused cases. As previously reported, a vast majority of Astroblastoma, MN1 altered patients are female, which we confirm for the BEND2-fused group (85%). The CXXC5-fused group, however, shows 75% male patients. Interestingly, 9/10 tumors of the few male patients observed in the BEND2-fused group were all located infratentorially or in the spinal cord, whereas almost all female cases show a supratentorial location (85/87). Histologically, the BEND2-fused group was primarily reported as Astroblastoma (39%), whereas in the CXXC5-fused cases, 31% CNS-PNET and only 8% Astroblastoma histologies were originally assigned. Preliminary clinical analyses showed that the BEND2-fused group has a relatively good 5/10-year OS of 97%/89%, but a less favorable 5/10-year PFS of 48%/35%, in line with previous studies. Patients showing CXXC5-fused tumors (n=8) indicated 5/10-year OS and PFS rates of 83%/83% and 60%/60%, respectively. Additional survival and molecular analyses are being conducted to further characterize Astroblastoma, MN1 altered tumors and its molecular subgroups.
IMMU-23. Novel gene-edited CAR-T cell therapy against Diffuse Intrinsic Pontine Glioma
Authors: Ilango Balakrishnan, Lillie Leach, Senthilnath Lakshmanachetty, Angela Pierce, Krishna Madhavan, Hannah Chatwin, Susan Fosmire, Christina Meadows, Adam Green, Terry Fry, Rajeev Vibhakar, Eric M Kohler, Sujatha Venkataraman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: We identified high expression of CD99 in DIPG tumors and developed a CAR using our newly identified single chain variable fragment (scFv) targeting CD99 incorporating a 4-1BB co-stimulatory domain. This CD99 CAR demonstrated the ability to dramatically shrink the established orthotopic DIPG tumor, however tumor recurrence remains an obstacle to cure, due to a loss of the CAR-T cells as they also express the target antigen, CD99 (fratricide). To overcome this obstacle, we modified these CAR-T by editing out CD99. METHODS: CD99 was knocked-out from the human T cells using CRISPR-cas9 gene-editing and subsequently transduced with our CD99 CAR-encoding virus, and isolated the pure population of CD99KO T-cells. These novel, gene-edited T-cells expressing CD99 CAR (“CD99KO CARs”) and the un-edited ones (“CD99 CAR”) were tested for tumor-lysis function when co-cultured with DIPG cells. DIPG tumor-bearing mice infused with a one-time dose of CD99KO CAR-T cells or CD99 CAR- or CD19 control CAR-T cells and were monitored for changes in the tumor burden. At the endpoint spleen and bone marrow were isolated to test for CAR+ cell persistence. RESULTS: The CD99KO CAR-T cells demonstrated effective tumor-lysis when co-cultured with DIPG cells. CD99KO CAR-T cells targeting CD99 showed complete clearance of DIPG tumor in orthotopic DIPG mouse models, and no tumor recurrence was seen well-beyond the time frame of expected tumor recurrence after treatment with un-edited CD99 CAR-T cells. There was an un-precedented increase in the xenograft survival, &amp;gt; 200 days, in mice treated with CD99KO CARs and at which time point sustained persistence of CAR+ cells were evident in the animal spleen and bone marrow. CONCLUSIONS: We have generated a new and promising CAR-T cell therapy that is effective against DIPG with enhanced persistence in animal models which is critical for clinical translation.
Leading countries in global science increasingly receive more citations than other countries doing similar research
Authors: Charles J. Gomez, Andrew C. Herman, Paolo Parigi
Journal: Nature Human Behaviour (2022)

Abstract Citations and text analysis are both used to study the distribution and flow of ideas between researchers, fields and countries, but the resulting flows are rarely equal. We argue that the differences in these two flows capture a growing global inequality in the production of scientific knowledge. We offer a framework called ‘citational lensing’ to identify where citations should appear between countries but are absent given that what is embedded in their published abstract texts is highly similar. This framework also identifies where citations are overabundant given lower similarity. Our data come from nearly 20 million papers across nearly 35 years and 150 fields from the Microsoft Academic Graph. We find that scientific communities increasingly centre research from highly active countries while overlooking work from peripheral countries. This inequality is likely to pose substantial challenges to the growth of novel ideas.
Whole genome germline sequencing: Its role in general health screening in family practice, the first study in the UK.
Authors: Ros A. Eeles, Michael Sandberg, Gabriella C. Pichert, Lucy Side, Tessa Homfray, Ann-Britt Jones, Sophie Hicks, Elizabeth Bancroft
Journal: Journal of Clinical Oncology (2022)

10510 Background: Whole genome sequencing (WGS) is now possible due to improvements in next generation sequencing technology. This gives the opportunity to incorporate genetic data into family practice health screening. The fulfilment of the potential of WGS lies in its future implementation into family practice. This study aimed to set up a model pathway to undertake WGS for actionable findings and assess its potential role in enhancing health screening. Methods: A pilot study comprised of 100 healthy participants from 2020-2022, recruited from a family practice, consented to routine baseline blood tests, cardiac assessment (ECG and echocardiogram), abdominopelvic ultrasound, all performed at the practice. Review of past medical, and family history was done from electronic health records (EHR). Germline genetic testing consisted of 84 cancer and 77 cardiac genes and whole genome sequencing (566 actionable genes reported), including higher penetrance monogenic mutations, recessive carrier alterations and pharmacogenomics. A multidisciplinary clinical team reviewed integrated results through an iterative process, which fed back to participants. Results: Twenty of 100 individuals (20%) had an actionable genetic variant in either cancer (10 individuals), thrombophilia (8) or cardiac rhythm disorder genes (2). Eighty percent of the participants had a variant in an autosomal recessive gene. Pharmacogenomics results yielded significant variants in 30%. Conclusions: The majority of patients had a significant change in management for themselves or their families. Whole genome sequencing as part of health screening in family practice is feasible and is likely to have significant beneficial health management implications. This study is the first of its kind in family practice and shows how this can be implemented.
Real-life trends of COVID-19 vaccination and outcomes among patients with cancer in Georgia: One center experience.
Authors: Tamar Esakia, Nino Balanchivadze, Ana Makashvili, Mariam Abuladze, Margarita Kacharava, Tamar Melkadze, Khatuna Tsiklauri, Elene Mariamidze, Sopio Tsitsilashvili, Nana Otkhozoria, Tamari Rukhadze
Journal: Journal of Clinical Oncology (2022)

e18753 Background: Vaccination against COVID-19 decreases the risk of severe COVID 19 disease, hospitalization and death. Despite widespread recommendation from different cancer societies, vaccine hesitancy remains an issue in developing countries. Methods: Records of patients with cancer who received COVID-19 vaccination from March 1, 2021 and December 1, 2021, at Todua Clinic were analyzed retrospectively. Patient reported adverse effects (AE), vaccine related treatment interruptions, COVID -19 infection, and hospitalization rates were recorded. Results: A total of 1728 patients with cancer were treated at Todua Clinic during the study period. Of 177 (10%) patients who received Covid-19 vaccine, 63% were female and 34% were male. All patients were White. Mean age was 62 years. Majority of patients had solid cancer (93%) and only 7% had hematologic malignancies. A total of 76 (43%) patients had metastatic disease. Nearly half (47%) of patients were receiving cytotoxic chemotherapy, while others were receiving different treatment modalities (hormone therapy (33%), concurrent chemo-radiation (9%), chemo-immunotherapy (4%), targeted therapy (3%), immune therapy (2%), radiation therapy (2%)). Majority of the patients were vaccinated during the treatment process (61%), while 18% received covid-19 vaccine prior to treatment initiation and 21% patients received the vaccine after completion of treatment. A total of 124 patients (70%) were vaccinated with Pfizer-BioNTech, 33(19%) patients had received Sinopharm (Beijing), 14(8%) patients were vaccinated with The Oxford/AstraZeneca and 6 (3%) patients with Sinovac/CoronaVac. Only 13 (7%) patients received a booster dose (BD). Injection site pain was main AE for all vaccines (AstraZeneca 50%, Pfizer 33%, Sinopharm 45%, Sinovac 50%). Fever was reported in 14% of patients vaccinated with AstraZeneca, and 2% of those who received Pfizer vaccine. There were isolated cases of lymphadenopathy, fatigue, loss of appetite, joint and muscle pain after Pfizer vaccine and one case of polyneuropathy after a booster dose (Pfizer). No treatment interruptions were attributed to vaccination. Only 23 patients (13%) had confirmed COVID-19 infection (post AstraZeneca 1, Pfizer 13, Sinopharm 8, Sinovac 1). Only 1 case of hospitalization was reported after Sinopharm vaccine. No death was reported due to COVID-19 infection. Majority of patients (80%) were vaccinated following recommendation from their treating oncologist. Conclusions: In our study, COVID-19 vaccination was found to be safe for patients with cancer, and performed well with only one COVID-19 related hospitalization and no deaths. Vaccination rates among cancer patients are marginal in Georgia, and institutional and national policies are needed.
Correction to: Circular RNA circERBB2 promotes gallbladder cancer progression by regulating PA2G4-dependent rDNA transcription
Authors: Xince Huang, Min He, Shuai Huang, Ruirong Lin, Ming Zhan, Dong Yang, Hui Shen, Sunwang Xu, Wei Cheng, Jianxiu Yu, Zilong Qiu, Jian Wang
Journal: Molecular Cancer (2022)
Preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: An open-label, randomized, phase II study.
Authors: Naoki Nakamura, Yuka Kato, Go Makimoto, Kiichiro Ninomiya, Daijiro Harada, Takashi Ninomiya, Isao Oze, Toshio Kubo, Masanori Fujii, Eiki Ichihara, Kadoaki Ohashi, Toshiyuki Kozuki, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2022)

TPS12141 Background: Paclitaxel is a taxane agent that has been used as a standard treatment for various malignancies. However, taxanes, such as paclitaxel, unfortunately cause a high frequency of chemotherapy-induced peripheral neuropathy (CIPN) as a result of axonal damage (All grade; 70%) (Clin Cancer Res.1996), CIPN worsens patients’ QOL and then lead to poor treatment compliance. Furthermore, there is no evidence for the prevention of CIPN. Goshajinkigan (GJG) is one of the Kampo medicine and it is approved in Japan for the treatment of numbness and has been commonly used for diabetic peripheral neuropathy. In addition, a non-clinical study has also shown the preventive effect of GJG against CIPN induced by paclitaxel (Molecular pain. 2014). To investigate if GJG indeed has a preventive effect for severe CIPN in patients receiving chemotherapy including paclitaxel, we started a two-arm randomized trial of GJG vs physician’s choice of treatment for patients. Methods: Patients have to meet the followings: pathologically diagnosed with malignant tumor (regardless of cancer type) and scheduled to receive ≥4 courses of chemotherapy including carboplatin and paclitaxel (paclitaxel ≥150mg/m 2 every 3-4 weeks) as initial chemotherapy; age ≥20yrs; Performance Status of 0 or 1. The primary endpoint is set as a proportion of ≥G2 CIPN by CTCAE ver.5.0 by the end of 4 courses of chemotherapy. With stratification by cancer type and age, patients will be randomized centrally to receive GJG at the same time as chemotherapy (A), or to receive the physician’s choice of treatment for pts if ≥G2 CIPN occurs without prophylaxis (B). Assuming that the incidence of ≥G2 CIPN would be 50% without prophylaxis and 20% with GJG prophylaxis, and assuming an 80% completion rate of four paclitaxel courses, the required sample size is 66 patients (1-β: 0.75, α: 0.1). The secondary endpoint includes time to the onset of CIPN G2, incidence rate and severity of CIPN at the end of each course, relative dose intensity of paclitaxel, adverse events other than CIPN. Enrollment began in 2022, and will be complete by 2025. Clinical trial information: 061210047.
Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy
Authors: Andrea G. Edlow, Victor M. Castro, Lydia L. Shook, Anjali J. Kaimal, Roy H. Perlis
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. <h3>Objective</h3> To evaluate whether in utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. <h3>Design, Setting, and Participants</h3> This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021. <h3>Exposures</h3> Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy. <h3>Main Outcomes and Measures</h3> Neurodevelopmental disorders determined from<i>International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10)</i>diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. <h3>Results</h3> The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (<i>P</i> = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79];<i>P</i> = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36];<i>P</i> = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44];<i>P</i> = .01). <h3>Conclusions and Relevance</h3> This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.